Patients with obstructive sleep apnea (OSA) experience repetitive collapses of the upper airway during sleep causing intermittent periods of hypoxia and hypercapnia (H/H) accompanied by arterial oxygen desaturations and increases in arterial carbon dioxide levels, ultimately altering both cardiac parasympathetic and sympathetic nervous system activity (Bradley and Floras, 2009; Leung, 2009; Loke et al., 2012). Upon termination of apneas, asphyxia causes a brief arousal from sleep, sympathetic activity increases and vagal tone decreases leading to surges in blood pressure (BP) and heart rate (HR) (Bradley and Floras, 2009; Leung, 2009; Loke et al., 2012). These acute effects of OSA are thought to cause chronic long term changes in cardiovascular dysfunction including hypertension, arrhythmias, and cardiovascular mortality (Bradley and Floras, 2009). Indeed, patients suffering from OSA have increases in blood pressure, lower heart rate variability, and reduced baroreflex sensitivity (Carlson et al., 1996; Trimer et al., 2013; Konecny et al., 2014), with chronic impairment in cardiac autonomic function i.e., sympathetic hyperactivity and diminished parasympathetic activity (Trimer et al. 2013). While identification of the mechanisms underlying the elevations in sympathetic nerve activity in CIH and OSA has been the focus of numerous studies (Fletcher et al., 1999; Fletcher et al., 2002; Kc et al., 2010; Zoccal et al., 2011); studies identifying the characteristics and mechanisms underlying depressed cardiac parasympathetic activity are scarce.
Exposure to chronic intermittent hypoxia (CIH) or hypoxia/hypercapnia (CIH/H) during the sleeping period of animals mimics the repetitive episodes of H/H that occur in humans with OSA and thus, serve as an animal model of OSA. Similar to what is observed in patients with OSA, animals exposed to CIH or CIH/H experience decreased baroreflex sensitivity, increased sympathetic activity, diminished parasympathetic activity to the heart, and develop hypertension within 3 weeks of CIH/H (Carlson et al, 1996; Dyavanapalli et al., 2014; Lai et al., 1985; Parish and Somers, 2004; Pinol et al., 2014).
The parasympathetic activity to heart arises from cardiac vagal neurons (CVNs) located in the nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMNX) that dominate the control of heart rate (Mendelowitz 1999) (FIG. 1). The preganglionic vagal efferent nerve terminals of the CVNs synapse with the postganglionic intracardiac ganglia neurons located within the connective and fat tissue surrounding sinoatrial and atrioventricular nodes (Armour 2008). CVNs are typically intrinsically silent and thus depend on synaptic inputs (glutamatergic, GABAergic, and glycinergic) to dictate their activity (Mendelowitz 1996; Willis et al. 1996; Neff et al. 1998; Wang et al. 2001; Wang et al. 2003).
The paraventricular nucleus of the hypothalamus (PVN) is critical in controlling autonomic function under normal conditions and regulating cardiovascular activity in response to hypoxic stress. The adverse alterations in BP, HR, and respiration that occur with CIH have been postulated to involve pathways from the PVN to sympathetic brainstem nuclei. Recently, it has been hypothesized that different PVN neurons projecting to parasympathetic nuclei, particularly the dorsal vagal complex (DVC) where parasympathetic cardiac control originates, differentially alter autonomic balance (Kc and Dick, 2010). However, much less is known concerning the function and role of the neurotransmission from the PVN to parasympathetic areas of the brainstem in normal and disease states. Consequently, there is a great need in the medical community for understanding the mechanisms underlying the parasympathetic control of cardiac dysfunction and for the development of novel therapeutic compounds, compositions, and methods of treatment, which help alleviate the aforementioned cardiorespiratory side effects associated with OSA.
The present disclosure investigates the mechanisms responsible for diminished parasympathetic control of cardiac functions during OSA and shows that oxytocin-secreting PVN neurons, as well as administration of oxytocin, are novel and powerful targets to mitigate important negative characteristics of the apnea as well as the adverse cardiorespiratory consequences of OSA.